ESTROGEN MODULATION OF HUMAN NOCICEPTORS

描述(申请人提供)：对多种疼痛障碍的临床研究表明，患者的生物性别是疼痛的常见风险因素，许多研究表明，在许多急慢性疾病中，女性疼痛的风险增加。这项拟议的转化性临床研究直接测试了以下假设：雌激素(172-E2)增加人类急性疼痛患者的外周伤害性感受器活性，以及雌激素受体的多态性与伤害性感受器活性增加和术后疼痛有关。为了解决这一假设，我们开发了一种方法来评估雌二醇对支配健康组织手术活检的外周人类伤害性感受器的胞吐活性的增强(评估支配第三磨牙牙髓的神经末梢的P物质(SP)释放)。我们的初步研究发现，雌激素受体1(ER1)和雌激素受体1(ER1)在手术活检的人三叉神经节神经元和外周神经元中都有表达，并发现雌二醇显著增加从女性采集的人体组织活检中由缓激肽/前列腺素E2(BK/PGE2)引起的isp，而从男性采集的组织活检中没有。此外，在A1修订中，我们报告了新的发现，ER1和ER2的某些多态性与这些患者术后疼痛强度的增加呈正相关。因此，我们提出了一个工作假说，即雌激素使人三叉神经伤害性感受器的外周终末敏感。为了评估这一假说，我们提出了以下目标：具体目标1：确定在BK/PGE2或辣椒素刺激下，女性和男性在增加SP释放方面是否存在差异。特定目标2：确定BK/PGE2或辣椒素刺激后循环雌二醇水平升高是否与SP释放增加相关。特定目标3：确定雌激素受体α(ER1)或β(ER2)的特定多态性是否与BK/PGE2或辣椒素诱导的暴露于雌二醇的外科活检组织中SP释放增加相关。具体目标4：建立一个数据库和基因库，为今后的遗传流行病学和药物遗传学研究提供便利。这个数据库将用于三个拟议的二次分析，包括评估ER基因多态和术后疼痛之间的关联，并将供其他研究人员使用，以促进NIH的数据共享政策。这些综合研究将从药理学、生化和遗传学水平评估雌激素对外周人类伤害性感受器的调节作用。总而言之，这些研究对雌激素受体激活增强女性伤害性感受器功能的假设进行了全面的评估。

DESCRIPTION (provided by applicant): Clinical studies of multiple pain disorders indicate that a patient's biological sex is a common risk factor for pain, with many studies demonstrating that women are at increased risk for pain in many acute and chronic conditions. The proposed translational clinical study directly tests the hypotheses that estradiol (172-E2) increases peripheral nociceptor activity in human acute pain patients and that polymorphisms of the estrogen receptors are associated with increased nociceptor activity and post-operative pain. To address this hypothesis, we have developed a method for evaluating estradiol enhancement of the exocytotic activity of peripheral human nociceptors innervating surgical biopsies of healthy tissue (evaluating substance P (SP) release from neuron terminals innervating dental pulp from extracted third molar teeth). Our preliminary studies identified estrogen receptor 1 (ER1) and ER1 in both human trigeminal ganglia neurons and in peripheral neurons in surgical biopsies, and discovered that estradiol significantly increases bradykinin/prostaglandin E2 (BK/PGE2)-evoked iSP from human tissue biopsies collected from women, but not from men. Moreover, in this A1 revision, we report new findings that certain polymorphisms of ER1 and ER2 are positively correlated with increased intensity of post-operative pain in these patients. Thus, we have developed a working hypothesis that estrogen sensitizes peripheral terminals of human trigeminal nociceptors. To evaluate this hypothesis, we propose the following aims: Specific Aim 1: Determine whether females differ from males for increased release of SP following stimulation with either BK/PGE2 or with capsaicin. Specific Aim 2: Determine whether elevated circulating estradiol levels are associated with increased release of SP following stimulation with either BK/PGE2 or with capsaicin Specific Aim 3: Determine whether specific polymorphisms of the estrogen receptor alpha (ER1) or beta (ER2) are associated with increased BK/PGE2- or capsaicin-evoked release of SP from surgical biopsies exposed to estradiol. Specific Aim 4: Establish a data and gene bank to facilitate future genetic epidemiological and pharmacogenetic studies. This database will be used for three proposed secondary analyses including an evaluation of the association between ER polymorphisms and post-surgical pain and will be also available to other investigators to foster the NIH policy for data sharing. These integrated studies will evaluate estrogen modulation of peripheral human nociceptors at the pharmacological, biochemical and genetic levels. Collectively, these studies provide a comprehensive evaluation of the hypothesis that activation of estrogen receptors enhances nociceptor function in women.